The PARP inhibitor Olaparib disrupts base excision repair of 5-aza-2′-deoxycytidine lesions

Decitabine (5-aza-21-deoxycytidine, 5-azadC) is used in the treatment of Myelodysplatic syndrome (MDS) and Acute Myeloid Leukemia (AML). Its mechanism of action is thought to involve reactivation of genes implicated in differentiation and transformation, as well as induction of DNA damage by trappin...

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Detalles Bibliográficos
Autores: Orta Vázquez, Manuel Luis, Calderón Montaño, José Manuel, Domínguez García, Inmaculada, Burgos Morón, Estefanía, Pastor Carrillo, Nuria María, López Lázaro, Miguel, Helleday, Thomas
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2014
País:España
Institución:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/41298
Acceso en línea:http://hdl.handle.net/11441/41298
https://doi.org/10.1093/nar/gku638
Access Level:acceso abierto
Palabra clave:5 aza 2' deoxycytidine
DNA
DNA methyltransferase 1
Nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase
Olaparib
XRCC1 protein
Descripción
Sumario:Decitabine (5-aza-21-deoxycytidine, 5-azadC) is used in the treatment of Myelodysplatic syndrome (MDS) and Acute Myeloid Leukemia (AML). Its mechanism of action is thought to involve reactivation of genes implicated in differentiation and transformation, as well as induction of DNA damage by trapping DNA methyltranferases (DNMT) to DNA. We demonstrate for the first time that base excision repair (BER) rec- ognizes 5-azadC-induced lesions in DNA and medi- ates repair. We find that BER (XRCC1) deficient cells are sensitive to 5-azadC and display an increased amount of DNA single- and double-strand breaks. The XRCC1 protein co-localizes with DNMT1 foci af- ter 5-azadC treatment, suggesting a novel and spe- cific role of XRCC1 in the repair of trapped DNMT1. 5-azadC-induced DNMT foci persist in XRCC1 defec- tive cells, demonstrating a role for XRCC1 in repair of 5-azadC-induced DNA lesions. Poly (ADP-ribose) polymerase (PARP) inhibition prevents XRCC1 relo- cation to DNA damage sites, disrupts XRCC1–DNMT1 co-localization and thereby efficient BER. In a panel of AML cell lines, combining 5-azadC and Olaparib cause synthetic lethality. These data suggest that PARP inhibitors can be used in combination with 5- azadC to improve treatment of MDS and AML.

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